A comprehensive multidisciplinary translational research program is proposed that will significantly improve the diagnosis, treatment and prevention of head and neck cancer while decreasing morbidity and mortality associated with this disease. The emphasis in this Specialized Program of Research Excellence (SPORE) is the development of innovative organ preservation treatment approaches that will reduce patient morbidity and to develop, test and incorporate sound prevention strategies with systemic treatment approaches that will address distant metastases and second primary cancers. Five proposed projects and three developmental projects will explore the molecular basis for chemotherapy and radiation treatment decisions (Projects 1, 2, 5) and the risk of distant metastases (Projects 3, 4, 5) or tumor recurrence/second primary cancer (Project 3). The overall hypothesis of this SPORE is that future advances in the treatment and prevention of head and neck cancer will be based on better understanding of specific molecular and genetic alterations characteristic of individual tumors. Based on this hypothesis, more specific and less morbid treatment regimens will be developed and tested that optimize organ preservation, prevention of recurrence and therapy of disseminated disease. Strong emphasis in this SPORE is placed on career development and pilot research project development to ensure ongoing innovation and increases in the numbers of new investigators dedicated to head and neck translational research. A limited number of critical infrastructure cores are also proposed. This Head and Neck SPORE is a fully integrated component of the University of Michigan Comprehensive Cancer Center. We propose extensive use of Cancer Center core facilities, clinical and laboratory resources and investigators, and draw heavily on experienced Cancer Center leadership. Superb teams of experienced clinical/basic collaborators combined with high institutional commitment and priority, and extensive patient resources provide an outstanding research environment that will ensure success in achieving overall SPORE goals.